title: Allelic interference: a mechanism for trans-dominant transmission of loss of function in the neurodegeneration of familial Alzheimer's disease.
abstract: Presenilins (PSs) are catalytic components of the γ-secretase complexes that promote the ε-cleavage of cell surface proteins producing cytosolic peptides shown to function in cell signaling and gene expression. In addition, secretase cleavages at γ-sites of amyloid precursor protein substrates produce the amyloid-β (Aβ) peptides found in all people. Aggregation of Aβ peptides form the amyloid fibrils found in amyloid plaques of Alzheimer's disease (AD) patients and aged individuals. A common hypothesis suggests that AD is caused by aggregated Aβ peptides, but treatments with either inhibitors of Aβ production or anti-Aβ antibodies showed no therapeutic value. Importantly, recent evidence [Marambaud et al.: Cell 2003;114:635-645] shows that PS familial AD (FAD) mutations cause a loss of γ-secretase cleavage function at the ε-site of substrates manifested by a decreased production of cytosolic peptides and an accumulation of transmembrane γ-secretase substrates. These data support the hypothesis that PS FAD mutations promote neurotoxicity by inhibiting the γ-secretase-catalyzed ε-cleavage of substrates, thus reducing cell signaling while causing accumulation of membrane-bound cytotoxic peptides. Similar mechanisms may be involved in toxicities observed in clinical trials of γ-secretase inhibitors. A model of allelic interference may explain the dominant negative transmission of neurotoxic loss of function in FAD neurodegeneration.
authors.affiliation: Departments of Psychiatry and Neuroscience, Center for Molecular Biology and Genetics of Neurodegeneration, Ican School of Medicine at Mount Sinai Medical Center, New York University, New York, N.Y., USA.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism; D053763:Presenilins / Q000235:genetics*
chemical_list: D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases